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Complex Regional Pain SyndromesKetCRPS-2NCT05212571

Long-term Pain Modulation by Intravenous Esketamine in CRPS

A study testing S-ketamine infusion inpatient setting and S-ketamine infusion outpatient setting in people with Complex Regional Pain Syndromes and CRPS (Complex Regional Pain Syndromes), run by Erasmus Medical Center at 1 site in Netherlands.

Enrolling by invitation

Enrolling by invitation. The study team selects and invites participants, usually from an existing group of patients.

Sites and contacts
Official record
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Trial summary

Intravenous administration of esketamine is an effective recognized therapeutic option in refractory pain in CRPS, which sometimes in at least a part of the patients has a prolonged therapeutic effect. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
S-ketamine infusion inpatient setting and S-ketamine infusion outpatient setting
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
60 participants
Where
1 siteNetherlands
Study dates
19 Apr 2022to 1 Oct 2027
Phase
Interventional
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Meeting the new International Association for the Study of Pain (IASP) diagnostic criteria for CRPS ("the Budapest Criteria) (Harden et al., 2010) or having met the new IASP diagnostic criteria of CRPS ("CRPS with Remission of Some features") (Goebel et al., 2021).
  • Willing and capable to participate in the study.
  • CRPS in one upper extremity and/or CRPS in one lower extremity
  • Treatment in an elective setting.
  • Adequate comprehension of the Dutch language
  • Age ≥ 18 years

Who cannot join

  • Severe liver disease
  • Psychiatric (schizophrenia, psychosis, delirium, manic depression)
  • Active substance abuse
  • Intoxication with alcohol or other substances
  • Poorly controlled hypertension
  • Unstable angina
Show all 13Show fewer
  • High-risk coronary vascular disease
  • Heart failure
  • Elevated intracranial pressure
  • Elevated intraocular pressure
  • Thyrotoxicosis
  • Pregnancy
  • Combination with derivates of xanthines (theophylline) or ergometrine

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Netherlands1 site

  • Erasmus MC

    Rotterdam, South Holland, 3000 CA

Other trials in Netherlands

About this study

Official title: Long-term Pain Modulation by Intravenous Esketamine in Complex Regional Pain Syndrome: a Non-inferiority Study

Intravenous administration of esketamine is an effective recognized therapeutic option in refractory pain in CRPS, which sometimes in at least a part of the patients has a prolonged therapeutic effect. Unfortunately, CRPS literature contains a wide range of ketamine dosing regimens with the result that clinical protocols on dosage and administration are very heterogeneous. The current esketamine regimen in Erasmus MC consists of a 6-day hospital admission for continuous administration. In the Netherlands, both inpatient and outpatient esketamine treatments are offered. Inpatient and outpatient ketamine treatments have never been compared in randomized controlled trials and it is therefore unknown whether these two dosing regimens are equally effective.

The primary objective is to demonstrate non-inferiority of experimental esketamine administration of 6x 1 day per 2 weeks (in total 3 months) as compared with standard esketamine administration of 1x 6 consecutive days. The end of study is at 6 months after the start of the study/treatment.

Read the detailed description

Rationale: Complex regional pain syndrome (CRPS) is a debilitating chronic pain condition of one or more limbs. Its diagnosis is based on (combinations of) underlying pathophysiological mechanisms. Achieving relevant pain relief fails in a significant proportion of CRPS patients. Intravenous administration of esketamine is an effective therapeutic option in refractory pain in CRPS, which in at least a part of the patients has a prolonged therapeutic effect. Unfortunately, CRPS literature contains a wide range of ketamine dosing regimens with the result that clinical protocols on dosage and administration are very heterogeneous. In the Netherlands, both inpatient and outpatient esketamine treatments are offered. The current esketamine regimen in Erasmus MC consists of a 6-day hospital admission for continuous administration; however, logistical boundaries limit this therapy. Esketamine infusions in an outpatient setting might increase flexibility and availability of esketamine treatment. However, inpatient and outpatient ketamine treatments have never been compared in randomized controlled trials and it is therefore unknown whether these two dosing regimens are equally effective.

Objective: The primary objective is to demonstrate non-inferiority of experimental esketamine administration of 6x 1 day per 2 weeks (in total 3 months) as compared with standard esketamine administration of 1x 6 consecutive days at 3 months after the start of the study/treatment. The secondary objective is to assess pain scores till 6 months follow-up, logistical problems, adverse effects, questionnaires, thermography and quantitative sensory testing in both treatment groups.

Study design: Prospective, randomized, non-inferiority study in 60 patients

Study population: Sixty adult patients with chronic pain due to CRPS

Intervention: All patients will receive intravenous esketamine. The standard treatment group receives intravenous esketamine for 6 consecutive days (in hospital). The experimental intervention group visits the outpatient clinic to receive intravenous esketamine in day-care setting every 2 weeks for 3 months.

Main study parameters/endpoints: The main study parameter is pain intensity, measured by means of Numerical Rating Scale (NRS), to demonstrate non-inferiority of the experimental treatment after three months.

Being tested
S-ketamine infusion inpatient setting, S-ketamine infusion outpatient setting
Keywords
CRPS, Complex Regional Pain Syndrome, ketamine, S-ketamine, esketamine
Medical subject headings
Complex Regional Pain Syndromes

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • S-ketamine infusion inpatient settingDrug

    Also called ketamine, esketamine

    S-ketamine is administered intravenously for six consecutive days. The administered dose of S-ketamine is 50 mcg/kg/h and can be increased to a maximum of 200 mcg/kg/h.

  • S-ketamine infusion outpatient settingDrug

    Also called ketamine, esketamine

    S-ketamine is administered intravenously for six hours. The administered dose of S-ketamine is 50 mcg/kg/h and can be increased to a maximum of 200 mcg/kg/h.

Study groups in NCT05212571
Study groupRoleWhat they receive
OutpatientExperimentalThe experimental intervention group visits the outpatient clinic to receive intravenous esketamine in day-care setting every 2 weeks for 3 months.
Receives: Drug: S-ketamine infusion outpatient setting
InpatientActive comparatorThe standard treatment group receives intravenous esketamine for 6 consecutive days in hospital.
Receives: Drug: S-ketamine infusion inpatient setting

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change from baseline pain scores

    Pain intensity measured by Numerical Rating Scale (NRS). Minimum value=0 and maximum value is 10. Higher scores mean a worse outcome.

    Measured: Baseline (week 0), During inpatient or outpatient esketamine infusion (week 1 for inpatient protocol / week 1, 3, 5, 7, 9, 11 for outpatient protocol), During telephone consultation (week 1, 3, 5, 7, 9, 11), Follow-up (3 months), End of study (6 months)

Secondary outcomes (11)

  1. Change from baseline Quantitative Sensory Testing

    To assess the sensory-discriminative dimensions of pain before and after ketamine treatment

    Measured: Baseline (week 0) and follow-up visit (week 12)

  2. Change from baseline Thermography

    Objectively measured effects on the extremity temperature by each of the administration regimens on symptoms vasomotor disturbances. The investigators use an infrared camera.

    Measured: Baseline (week 0) and follow-up visit (week 12)

  3. Adverse events due to S-ketamine infusion

    Assessed by physical examination and vital parameters (blood pressure, heart rate, saturation and temperature)

    Measured: During inpatient or outpatient esketamine infusion (week 1 for inpatient protocol / week 1, 3, 5, 7, 9, 11 for outpatient protocol), During telephone consultation (week 1, 3, 5, 7, 9, 11)

  4. Change from baseline pain medication dose

    Measured: Baseline (week 0), follow-up visit (3 months) and end of study (6 months)

  5. Change from baseline Complex Regional Pain Syndrome severity score

    according to Harden et al. (2010). All symptoms and signs are scored as Yes = 1 and No = 0. Sum up the total score (i.e., number of "Yes" responses) to derive the total CSS score. The Complex Severity Score can range from 0-16. Higher scores mean a worse outcome.

    Measured: Baseline (week 0) and follow-up visit (3 months)

  6. Global Perceived Effect

    The Global Perceived Effect asks the patient to rate, on a numerical scale 0-7, how much their condition has improved or deteriorated since some predefined time point. Higher scores mean a worse outcome. According to Hudak et al. 2000.

    Measured: During telephone consultation (week 1, 3, 5, 7, 9, 11), follow-up visit (3 months) and end of study (6 months)

  7. Patient-Reported Outcomes Measurement Information System (PROMIS) -29 Profile

    Assesses 7 domains, each with 4 questions (ranging from 1-5, ranging from no/never/not at all to yes/always/continuously): depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles and activities. According to Terwee et al. 2014

    Measured: Baseline (week 0) and follow-up visit (3 months)

  8. Short-form McGill Pain Questionnaire-2

    Neuropathic pain items capturing the quality of pain. Scale ranging from 0-10. Higher scores mean a worse outcome. According to Dworkin et al., 2009

    Measured: Baseline (week 0) and follow-up visit (3 months)

  9. Pain Catastrophizing Scale

    The respondent considers how confident they are performing each activity, while taking their pain into account. Scale from 0-4. Higher scores mean a worse outcome. According to Sullivan et al., 2011

    Measured: Baseline (week 0) and follow-up visit (3 months)

  10. EQ-5D-5L.

    To measure health state, comprising mobility, self-care, usual activities, pain/discomfort, anxiety/depression.

    The 5 questions about health status are scored on a 5-point scale (1-5) Placing these numbers one after the other creates a 5-digit index that represents a health profile (eg 12323). According to Herdman et al., 2011

    Measured: Baseline (week 0) and follow-up visit (3 months)

  11. Pain Self-Efficacy Questionnaire

    The respondent considers how confident they are performing each activity, while taking their pain into account. The scale ranges from 0-6. Higher scores mean a better outcome. According to Nicholas et al., 2007

    Measured: Baseline (week 0) and follow-up visit (3 months)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Jan 2022
  2. Study start19 Apr 2022
  3. Primary completion1 Oct 2026 (estimated)
  4. Study completion1 Oct 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
prospective, randomized non-inferiority study
Masking
None (open label)
Enrolment
60 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05212571
Sponsor's protocol ID
NL77785.078.21
Other IDs
2021-000640-21, MEC-2021-0426
Acronym
KetCRPS-2
Status last verified
Sep 2023
First submitted
13 Dec 2021
Last updated
11 Sep 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • Sigtermans MJ, van Hilten JJ, Bauer MCR, Arbous SM, Marinus J, Sarton EY, Dahan A. Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. 2009 Oct;145(3):304-311. doi: 10.1016/j.pain.2009.06.023. Epub 2009 Jul 14.

    PubMed 19604642

  • Mangnus TJP, Bharwani KD, Stronks DL, Dirckx M, Huygen FJPM. Ketamine therapy for chronic pain in The Netherlands: a nationwide survey. Scand J Pain. 2021 Aug 24;22(1):97-105. doi: 10.1515/sjpain-2021-0079. Print 2022 Jan 27.

    PubMed 34432970

  • Mangnus TJP, Dirckx M, Bharwani KD, de Vos CC, Frankema SPG, Stronks DL, Huygen FJPM. Effect of intravenous low-dose S-ketamine on pain in patients with Complex Regional Pain Syndrome: A retrospective cohort study. Pain Pract. 2021 Nov;21(8):890-897. doi: 10.1111/papr.13056. Epub 2021 Jul 24.

    PubMed 34233070

  • Harden NR, Bruehl S, Perez RSGM, Birklein F, Marinus J, Maihofner C, Lubenow T, Buvanendran A, Mackey S, Graciosa J, Mogilevski M, Ramsden C, Chont M, Vatine JJ. Validation of proposed diagnostic criteria (the "Budapest Criteria") for Complex Regional Pain Syndrome. Pain. 2010 Aug;150(2):268-274. doi: 10.1016/j.pain.2010.04.030. Epub 2010 May 20.

    PubMed 20493633

  • Grieve S, Perez RSGM, Birklein F, Brunner F, Bruehl S, Harden RN, Packham T, Gobeil F, Haigh R, Holly J, Terkelsen A, Davies L, Lewis J, Thomassen I, Connett R, Worth T, Vatine JJ, McCabe CS. Recommendations for a first Core Outcome Measurement set for complex regional PAin syndrome Clinical sTudies (COMPACT). Pain. 2017 Jun;158(6):1083-1090. doi: 10.1097/j.pain.0000000000000866.

    PubMed 28178071

  • Goebel A, Birklein F, Brunner F, Clark JD, Gierthmuhlen J, Harden N, Huygen F, Knudsen L, McCabe C, Lewis J, Maihofner C, Magerl W, Moseley GL, Terkelsen A, Thomassen I, Bruehl S. The Valencia consensus-based adaptation of the IASP complex regional pain syndrome diagnostic criteria. Pain. 2021 Sep 1;162(9):2346-2348. doi: 10.1097/j.pain.0000000000002245. No abstract available.

    PubMed 33729210

  • Cohen SP, Bhatia A, Buvanendran A, Schwenk ES, Wasan AD, Hurley RW, Viscusi ER, Narouze S, Davis FN, Ritchie EC, Lubenow TR, Hooten WM. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Chronic Pain From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018 Jul;43(5):521-546. doi: 10.1097/AAP.0000000000000808.

    PubMed 29870458

  • Zhao J, Wang Y, Wang D. The Effect of Ketamine Infusion in the Treatment of Complex Regional Pain Syndrome: a Systemic Review and Meta-analysis. Curr Pain Headache Rep. 2018 Feb 5;22(2):12. doi: 10.1007/s11916-018-0664-x.

    PubMed 29404715

  • Harden NR, Bruehl S, Perez RSGM, Birklein F, Marinus J, Maihofner C, Lubenow T, Buvanendran A, Mackey S, Graciosa J, Mogilevski M, Ramsden C, Schlereth T, Chont M, Vatine JJ. Development of a severity score for CRPS. Pain. 2010 Dec;151(3):870-876. doi: 10.1016/j.pain.2010.09.031. Epub 2010 Oct 20.

    PubMed 20965657

  • Hudak PL, Wright JG. The characteristics of patient satisfaction measures. Spine (Phila Pa 1976). 2000 Dec 15;25(24):3167-77. doi: 10.1097/00007632-200012150-00012.

    PubMed 11124733

  • Terwee CB, Roorda LD, de Vet HC, Dekker J, Westhovens R, van Leeuwen J, Cella D, Correia H, Arnold B, Perez B, Boers M. Dutch-Flemish translation of 17 item banks from the patient-reported outcomes measurement information system (PROMIS). Qual Life Res. 2014 Aug;23(6):1733-41. doi: 10.1007/s11136-013-0611-6. Epub 2014 Jan 9.

    PubMed 24402179

  • Dworkin RH, Turk DC, Revicki DA, Harding G, Coyne KS, Peirce-Sandner S, Bhagwat D, Everton D, Burke LB, Cowan P, Farrar JT, Hertz S, Max MB, Rappaport BA, Melzack R. Development and initial validation of an expanded and revised version of the Short-form McGill Pain Questionnaire (SF-MPQ-2). Pain. 2009 Jul;144(1-2):35-42. doi: 10.1016/j.pain.2009.02.007. Epub 2009 Apr 7.

    PubMed 19356853

  • Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011 Dec;20(10):1727-36. doi: 10.1007/s11136-011-9903-x. Epub 2011 Apr 9.

    PubMed 21479777

  • Nicholas MK. The pain self-efficacy questionnaire: Taking pain into account. Eur J Pain. 2007 Feb;11(2):153-63. doi: 10.1016/j.ejpain.2005.12.008. Epub 2006 Jan 30.

    PubMed 16446108

  • Mangnus TJP, Bharwani KD, Dirckx M, Huygen FJPM. From a Symptom-Based to a Mechanism-Based Pharmacotherapeutic Treatment in Complex Regional Pain Syndrome. Drugs. 2022 Apr;82(5):511-531. doi: 10.1007/s40265-022-01685-4. Epub 2022 Mar 5.

    PubMed 35247200

Questions about this trial

What is this clinical trial studying?

A study testing S-ketamine infusion inpatient setting and S-ketamine infusion outpatient setting in people with Complex Regional Pain Syndromes and CRPS (Complex Regional Pain Syndromes), run by Erasmus Medical Center at 1 site in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: enrolling by invitation, as of the sponsor's last update on 11 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change from baseline pain scores (time frame: Baseline (week 0), During inpatient or outpatient esketamine infusion (week 1 for inpatient protocol / week 1, 3, 5, 7, 9, 11 for outpatient protocol), During telephone consultation (week 1, 3, 5, 7, 9, 11), Follow-up (3 months), End of study (6 months)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05212571, which also lists 16 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Sep 2023.

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